TMPRSS2-ERG and other gene fusions involving ETS factors and genes with strong promoter elements are common in prostate cancer. Although ERG activation has been linked to invasive properties of ...prostate cancers, the precise mechanisms and pathways of ERG-mediated oncogenesis remain poorly understood. Here, we show that ERG knockdown in VCaP prostate cancer cells causes an activation of cell adhesion, resulting in strongly induced active beta(1)-integrin and E-cadherin expression as well as changes in WNT signaling. These observations were corroborated by data from ERG-overexpressing nontransformed prostate epithelial cells as well as gene expression data from clinical prostate cancer samples, which both indicated a link between ERG and epithelial-to-mesenchymal transition (EMT). Upregulation of several WNT pathway members was seen in ERG-positive prostate cancers, with frizzled-4 (FZD4) showing the strongest overexpression as verified by both reverse transcription-PCR and immunostaining. Both ERG knockin and knockdown modulated the levels of FZD4 expression. FZD4 silencing could mimic the ERG knockdown phenotype by inducing active beta(1)-integrin and E-cadherin expression, whereas FZD4 overexpression reversed the phenotypic effects seen with ERG knockdown. Taken together, our results provide mechanistic insights to ERG oncogenesis in prostate cancer, involving activation of WNT signaling through FZD4, leading to cancer-promoting phenotypic effects, including EMT and loss of cell adhesion.
Current treatment options for advanced and hormone refractory prostate cancer are limited and responses to commonly used androgen pathway inhibitors are often unsatisfactory. Our recent results ...indicated that sodium ionophore monensin is one of the most potent and cancer-specific inhibitors in a systematic sensitivity testing of most known drugs and drug-like molecules in a panel of prostate cancer cell models. Because monensin has been extensively used in veterinary applications to build muscle mass in cattle, the link to prostate cancer and androgen signaling was particularly interesting. Here, we showed that monensin effects at nanomolar concentrations are linked to induction of apoptosis and potent reduction of androgen receptor mRNA and protein in prostate cancer cells. Monensin also elevated intracellular oxidative stress in prostate cancer cells as evidenced by increased generation of intracellular reactive oxygen species and by induction of a transcriptional profile characteristic of an oxidative stress response. Importantly, the antiproliferative effects of monensin were potentiated by combinatorial treatment with the antiandrogens and antagonized by antioxidant vitamin C. Taken together, our results suggest monensin as a potential well-tolerated, in vivo compatible drug with strong proapoptotic effects in prostate cancer cells, and synergistic effects with antiandrogens. Moreover, our data suggest a general strategy by which the effects of antiandrogens could be enhanced by combinatorial administration with agents that increase oxidative stress in prostate cancer cells.
Approximately 20% of patients with renal cell carcinoma (RCC) present with primarily metastatic disease and over 30% of patients with localized RCC will develop distant metastases later, after ...complete resection of the primary tumor. Accurate postoperative prognostic models are essential for designing personalized surveillance programs, as well as for designing adjuvant therapy and trials. Several clinical and histopathological prognostic factors have been identified and adopted into prognostic algorithms to assess the individual risk for disease recurrence after radical or partial nephrectomy. However, the prediction accuracy of current prognostic models has been studied in retrospective patient cohorts and the optimal set of prognostic features remains unclear. In addition to traditional histopathological prognostic factors, novel biomarkers, such as gene expression profiles and circulating tumor DNA, are extensively studied to supplement existing prognostic algorithms to improve their prediction accuracy. Here, we aim to give an overview of existing prognostic features and prediction models for localized postoperative clear cell RCC and discuss their role in the adjuvant therapy trials. The results of ongoing placebo-controlled adjuvant therapy trials may elucidate prognostic factors and biomarkers that help to define patients at high risk for disease recurrence.
Purpose: To identify novel therapeutic opportunities for patients with prostate cancer, we applied high-throughput screening to systematically
explore most currently marketed drugs and drug-like ...molecules for their efficacy against a panel of prostate cancer cells.
Experimental Design: We carried out a high-throughput cell-based screening with proliferation as a primary end-point using a library of 4,910
drug-like small molecule compounds in four prostate cancer (VCaP, LNCaP, DU 145, and PC-3) and two nonmalignant prostate epithelial
cell lines (RWPE-1 and EP156T). The EC 50 values were determined for each cell type to identify cancer selective compounds. The in vivo effect of disulfiram (DSF) was studied in VCaP cell xenografts, and gene microarray and combinatorial studies with copper
or zinc were done in vitro for mechanistic exploration.
Results: Most of the effective compounds, including antineoplastic agents, were nonselective and found to inhibit both cancer and
control cells in equal amounts. In contrast, histone deacetylase inhibitor trichostatin A, thiram, DSF, and monensin were
identified as selective antineoplastic agents that inhibited VCaP and LNCaP cell proliferation at nanomolar concentrations.
DSF reduced tumor growth in vivo , induced metallothionein expression, and reduced DNA replication by downregulating MCM mRNA expression. The effect of DSF
was potentiated by copper in vitro .
Conclusions: We identified three novel cancer-selective growth inhibitory compounds for human prostate cancer cells among marketed drugs.
We then validated DSF as a potential prostate cancer therapeutic agent. These kinds of pharmacologically well-known molecules
can be readily translated to in vivo preclinical studies and clinical trials. (Clin Cancer Res 2009;15(19):6070â8)
Metastases of distant primary tumors on the parotid gland are very rare. Tumor‐to‐tumor metastasis to salivary gland tumors is extremely rare. A case of a 69‐year‐old woman with a large left parotid ...gland mass with no previous salivary gland problems or cancer. Fine‐needle aspiration (FNA) showed evidence of a Warthin tumor. A total left parotidectomy was performed. The final pathology report showed a Warthin tumor containing two metastases of adenocarcinoma. The immunohistochemistry of the metastases led to the diagnosis of primary breast cancer. A negative FNA does not rule out the possibility of a malignant parotid tumor or metastasis, and a parotid lump should be presumed to be a secondary tumor until proven otherwise if the patient has a history of any distant primary cancer. Our patient case serves as a reminder that a new distant primary cancer might be the cause of a parotid lump.
Tumor‐to‐tumor metastasis to salivary gland tumors is extremely rare. We present a case in which lobular breast carcinoma metastases were found within a Warthin tumor of the left parotid gland. The pathology of the distant metastases steered the diagnostics of the primary breast tumor. This patient case serves as a reminder that a new distant primary cancer might be the cause of a parotid lump.
Our knowledge on tissue- and disease-specific functions of human genes is rather limited and highly context-specific. Here, we have developed a method for the comparison of mRNA expression levels of ...most human genes across 9,783 Affymetrix gene expression array experiments representing 43 normal human tissue types, 68 cancer types, and 64 other diseases. This database of gene expression patterns in normal human tissues and pathological conditions covers 113 million datapoints and is available from the GeneSapiens website.
The arachidonic acid and prostaglandin pathway has been implicated in prostate carcinogenesis, but comprehensive studies of the individual members in this key pathway are lacking. Here, we first ...conducted a systematic bioinformatic study of the expression of 36 arachidonic acid pathway genes across 9783 human tissue samples. The results showed that the PLA2G7 , HPGD , EPHX2 , and CYP4F8 genes are highly expressed in prostate cancer. Functional studies using RNA interference in prostate cancer cells indicated that all four genes are also essential for cell growth and survival. Clinical validation confirmed high PLA2G7 expression, especially in ERG oncogene-positive prostate cancers, and its silencing sensitized ERG -positive prostate cancer cells to oxidative stress. HPGD was highly expressed in androgen receptor (AR)-overexpressing advanced tumors, as well as in metastatic prostate cancers. EPHX2 mRNA correlated with AR in primary prostate cancers, and its inhibition in vitro reduced AR signaling and potentiated the effect of antiandrogen flutamide in cultured prostate cancer cells. In summary, we identified four novel putative therapeutic targets with biomarker potential for different subtypes of prostate cancer. In addition, our results indicate that inhibition of these enzymes may be particularly powerful when combined with other treatments, such as androgen deprivation or induction of oxidative stress.
After surgery of localized renal cell carcinoma, over 20% of the patients will develop distant metastases. Our aim was to develop an easy-to-use prognostic model for predicting metastasis-free ...survival after radical or partial nephrectomy of localized clear cell RCC. Model training was performed on 196 patients. Right-censored metastasis-free survival was analysed using LASSO-regularized Cox regression, which identified three key prediction features. The model was validated in an external cohort of 714 patients. 55 (28%) and 134 (19%) patients developed distant metastases during the median postoperative follow-up of 6.3 years (interquartile range 3.4-8.6) and 5.4 years (4.0-7.6) in the training and validation cohort, respectively. Patients were stratified into clinically meaningful risk categories using only three features: tumor size, tumor grade and microvascular invasion, and a representative nomogram and a visual prediction surface were constructed using these features in Cox proportional hazards model. Concordance indices in the training and validation cohorts were 0.755 ± 0.029 and 0.836 ± 0.015 for our novel model, which were comparable to the C-indices of the original Leibovich prediction model (0.734 ± 0.035 and 0.848 ± 0.017, respectively). Thus, the presented model retains high accuracy while requiring only three features that are routinely collected and widely available.
Prostate cancer is a heterogeneous group of diseases and there is a need for more efficient and targeted methods of treatment. In this study, the potential of gene expression data and RNA ...interference technique were combined to advance future personalized prostate cancer therapeutics. To distinguish the most promising in vivo prevalidated prostate cancer drug targets, a bioinformatic analysis was carried out using genome-wide gene expression data from 9873 human tissue samples. In total, 295 genes were selected for further functional studies in cultured prostate cancer cells due to their high mRNA expression in prostate, prostate cancer or in metastatic prostate cancer samples. Second, RNAi based cell viability assay was performed in VCaP and LNCaP prostate cancer cells. Based on the siRNA results, gene expression patterns in human tissues and novelty, endoplasmic reticulum function associated targets AIM1, ERGIC1 and TMED3, as well as mitosis regulating TPX2 were selected for further validation. AIM1, ERGIC1, and TPX2 were shown to be highly expressed especially in prostate cancer tissues, and high mRNA expression of ERGIC1 and TMED3 associated with AR and ERG oncogene expression. ERGIC1 silencing specifically regulated the proliferation of ERG oncogene positive prostate cancer cells and inhibited ERG mRNA expression in these cells, indicating that it is a potent drug target in ERG positive subgroup of prostate cancers. TPX2 expression associated with PSA failure and TPX2 silencing reduced PSA expression, indicating that TPX2 regulates androgen receptor mediated signaling. In conclusion, the combinatorial usage of microarray and RNAi techniques yielded in a large number of potential novel biomarkers and therapeutic targets, for future development of targeted and personalized approaches for prostate cancer management.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Hypoxia inducible factors, HIF‐1α and HIF‐2α, and their main regulators, the prolyl hydroxylase domain proteins (PHDs), mediate cellular response to hypoxia and contribute to tumor ...progression in clear cell renal cell carcinoma (ccRCC). These biomarkers may improve the value of traditional histopathological features in predicting disease progression after nephrectomy for localized ccRCC and guide patient selection for adjuvant treatments.
Patients and Methods
In this study, we analyzed the associations of PHD2 and PHD3 with histopathological tumor features and recurrence‐free survival (RFS) in a retrospective cohort of 173 patients who had undergone surgery for localized ccRCC at Helsinki University Hospital (HUH), Finland. An external validation cohort of 191 patients was obtained from Turku University Hospital (TUH), Finland. Tissue‐microarrays (TMA) were constructed using the primary tumor samples. Clinical parameters and follow‐up information from 2006 to 2019 were obtained from electronic medical records. The cytoplasmic and nuclear expression of PHD2, and PHD3 were scored based on immunohistochemical staining and their associations with histopathological features and RFS were evaluated.
Results
Nuclear PHD2 and PHD3 expression in cancer cells were associated with lower pT‐stage and Fuhrman grade compared with negative nuclei. Patients with positive nuclear expression of PHD2 and PHD3 in cancer cells had favorable RFS compared with patients having negative tumors. The nuclear expression of PHD2 was independently associated with a decreased risk of disease recurrence or death from RCC in multivariable analysis. These results were observed in both cohorts.
Conclusions
The absence of nuclear PHD2 and PHD3 expression in ccRCC was associated with poor RFS and the nuclear expression of PHD2 predicted RFS regardless of other known histopathological prognostic factors. Nuclear PHD2 and PHD3 are potential prognostic biomarkers in patients with localized ccRCC and should be further investigated and validated in prospective studies.
The prolyl hydroxylase domain proteins (PHDs) mediate cellular response to hypoxia and contribute to tumor progression in clear cell renal cell carcinoma (ccRCC). In our externally validated study, we analyzed the association of PHD2&3 with tumor features and recurrence free survival (RFS). Our findings suggest, that PHD2 and PHD3 are associated with poor prognosis in clear cell renal cell carcinoma (ccRCC) and are valuable prognostic biomarkers in localized ccRCC.
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